Papilozumib Vaginal Gel for Exocervical Mucosal Restoration in Women With Human Papillomavirus (HPV)

Participants receive Papilozumib® vaginal gel for 6 months. During the first 3 months, one single-dose vaginal applicator is administered daily for 21 days followed by 7 days without treatment. During the following 3 months, one applicator is administered on alternate days, excluding menstrual periods

Papilozumib® is a single-dose vaginal gel administered for 6 months. During the first 3 months, participants apply one vaginal applicator daily for 21 days followed by 7 days without treatment. During the following 3 months, participants apply one applicator on alternate days, excluding menstrual periods.

Participants receive Papilozumib® vaginal gel for 6 months using the same regimen as the vaginal-gel-only arm. Participants also receive oral Papilozumib® for 6 months, administered as two capsules while fasting and one capsule before dinner each day, separated from meals.

Papilozumib® is a single-dose vaginal gel administered for 6 months. During the first 3 months, participants apply one vaginal applicator daily for 21 days followed by 7 days without treatment. During the following 3 months, participants apply one applicator on alternate days, excluding menstrual periods.

Papilozumib® oral supplement is provided as capsules containing mushroom extracts, vitamins, minerals, and probiotics. Participants take three capsules daily for 6 months: two capsules while fasting and one capsule before dinner, separated from meals.

Participants receive usual clinical practice without Papilozumib® vaginal gel or oral Papilozumib® supplementation. Participants undergo the study assessments and follow-up procedures specified in the protocol.

Exocervical mucosal restoration will be assessed by colposcopy in participants assigned to Papilozumib® vaginal gel alone. The investigator will score the exocervical mucosa using a 5-point scale: 1, severe ectopia with bleeding; 2, severe or extensive ectopia involving more than 50% from the external cervical opening; 3, moderate ectopia involving 25% to 50%; 4, mild ectopia involving less than 25%; and 5, no ectopia. Higher scores indicate greater exocervical mucosal restoration.

In participants assigned to Papilozumib® vaginal gel alone, the investigator will record whether the cervical cytology result is concordant with the colposcopic finding using a "Yes" or "No" response. The outcome will be reported as the percentage of participants with concordant findings.

Exocervical mucosal restoration will be assessed by colposcopy using the 5-point scale: 1, severe ectopia with bleeding; 2, severe or extensive ectopia involving more than 50%; 3, moderate ectopia involving 25% to 50%; 4, mild ectopia involving less than 25%; and 5, no ectopia. Higher scores indicate greater mucosal restoration. The Day 30 assessment applies to the vaginal gel plus oral supplement arm and the usual clinical practice arm. Month 3 and Month 6 assessments apply to all study arms.

The investigator will record whether the cervical cytology result is concordant with the colposcopic finding using a Yes or No response. The outcome will be reported as the percentage of participants with concordant findings. The Day 30 assessment applies to Arms B and C, and the Month 3 and Month 6 assessments apply to all arms.

Among participants with abnormal cervical cytology at baseline, normalization is defined as a change from atypical squamous cells of undetermined significance (ASC-US), low-grade squamous intraepithelial lesion (LSIL), or atypical glandular cells (AGC) to normal cervical cytology, with a concordant colposcopic finding. The reported outcome will be the percentage of participants meeting this combined definition of cytological normalization; colposcopic concordance will not be reported as a separate measurement within this outcome.

Complete human papillomavirus clearance will be assessed using genotyped polymerase chain reaction (PCR) testing. Complete clearance is defined as a negative HPV test or disappearance of all HPV genotypes detected at baseline. The reported value will be the percentage of participants meeting the definition of complete HPV clearance.

Partial human papillomavirus clearance will be assessed using genotyped polymerase chain reaction (PCR) testing. Partial clearance is defined as disappearance of at least one HPV genotype detected at baseline. The reported value will be the percentage of participants meeting the definition of partial HPV clearance.

Vaginal health will be assessed using the Bachmann Vaginal Health Index. The change from the baseline score will be calculated at each follow-up assessment.

Participants in the two treatment arms will rate their satisfaction with the assigned treatment using a 7-point response scale ranging from 1, satisfied, to 7, not at all satisfied. Lower scores indicate greater satisfaction.

Adherence to Papilozumib vaginal gel will be assessed in participants assigned to Arms A and B using treatment dispensing and return records and the participant treatment calendar. Vaginal gel adherence will be categorized as poor, less than 50%; moderate, 50% to less than 75%; good, 75% to less than 90%; or very good, 90% or greater.

Adherence to the Papilozumib oral supplement will be assessed in participants assigned to Arm B using treatment dispensing and return records and the participant treatment calendar. Oral supplement adherence will be categorized as poor, less than 50%; moderate, 50% to less than 75%; good, 75% to less than 90%; or very good, 90% or greater.

Safety will be assessed as the number of participants who experience at least one adverse event after randomization. A participant will be counted once in this outcome regardless of the number of adverse events experienced. Characteristics of individual adverse events, including their nature and severity, will be evaluated descriptively and are not separate measurements within this Outcome Measure.

Participants in the two treatment arms will rate tolerability using a 5-point scale: 1, very good; 2, good; 3, neutral; 4, poor; and 5, very poor. Arm A participants will rate the vaginal gel, and Arm B participants will rate the vaginal gel plus oral supplement combination. Lower scores indicate better tolerability.

Vaginal microbiota will be assessed by shotgun metagenomic sequencing and classified according to Community State Type (CST). Categories are: CST I, dominated by Lactobacillus crispatus; CST II, dominated by Lactobacillus gasseri; CST III, dominated by Lactobacillus iners; CST IV, characterized by low Lactobacillus abundance and the presence of anaerobic and facultative anaerobic microorganisms; and CST V, dominated by Lactobacillus jensenii. The distribution of participants across CST categories will be reported at each assessment.

Intestinal microbiota will be assessed in stool samples using shotgun metagenomic sequencing. Microbial diversity will be summarized using the Shannon diversity index. The Shannon diversity index will be reported at each assessment, with higher values indicating greater microbial diversity.